Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Florida, USA.
Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc, Kenilworth, NJ, USA.
Sci Rep. 2023 Feb 22;13(1):3100. doi: 10.1038/s41598-023-29964-4.
Despite high anticancer activity, doxorubicin (DOX)-induced cardiotoxicity (DIC) limits the extensive utility of DOX in a clinical setting. Amongst various strategies explored, dexrazoxane (DEX) remains the only cardioprotective agent to be approved for DIC. In addition, altering the dosing regimen of DOX has also proved to be somewhat beneficial in decreasing the risk of DIC. However, both approaches have limitations and further studies are required to better optimize them for maximal beneficial effects. In the present work, we quantitatively characterized DIC as well as the protective effects of DEX in an in vitro model of human cardiomyocytes, by means of experimental data and mathematical modeling and simulation (M&S) approaches. We developed a cellular-level, mathematical toxicodynamic (TD) model to capture the dynamic in vitro drug-drug interaction, and relevant parameters associated with DIC and DEX cardio-protection were estimated. Subsequently, we executed in vitro-in vivo translation by simulating clinical PK profiles for different dosing regimens of DOX alone and in combinations with DEX and using the simulated PK profiles to drive the cell-based TD models to evaluate the effects of long-term, clinical dosing regimens of these drugs on the relative cell viability of AC16 and to determine optimal drug combinations with minimal cellular toxicity. Here, we identified that the Q3W (once every three weeks) DOX regimen with 10:1 DEX:DOX dose ratio over three cycles (nine weeks) may offer maximal cardio-protection. Overall, the cell-based TD model can be effectively used to better design subsequent preclinical in vivo studies aimed for further optimizing safe and effective DOX and DEX combinations to mitigate DIC.
尽管阿霉素（DOX）具有很高的抗癌活性，但 DOX 诱导的心脏毒性（DIC）限制了 DOX 在临床环境中的广泛应用。在探索的各种策略中，右雷佐生（DEX）仍然是唯一被批准用于 DIC 的心脏保护剂。此外，改变 DOX 的剂量方案也被证明在降低 DIC 风险方面有一定的益处。然而，这两种方法都有其局限性，需要进一步的研究来更好地优化它们，以获得最大的有益效果。在本工作中，我们通过实验数据和数学建模与模拟（M&S）方法，在人心肌细胞的体外模型中定量表征了 DIC 以及 DEX 的保护作用。我们开发了一个细胞水平的毒代动力学（TD）模型来捕捉体外药物相互作用的动态，并估计了与 DIC 和 DEX 心脏保护相关的相关参数。随后，我们通过模拟不同 DOX 单独和与 DEX 联合使用的临床 PK 曲线，并使用模拟的 PK 曲线来驱动基于细胞的 TD 模型，以评估这些药物的长期临床剂量方案对 AC16 相对细胞活力的影响，并确定具有最小细胞毒性的最佳药物组合。在这里，我们确定 Q3W（每三周一次）DOX 方案与 10:1 的 DEX:DOX 剂量比在三个周期（九周）中可能提供最大的心脏保护作用。总的来说，基于细胞的 TD 模型可以有效地用于更好地设计后续的临床前体内研究，旨在进一步优化安全有效的 DOX 和 DEX 组合，以减轻 DIC。
